BRCA1 expression modulates chemosensitivity of BRCA1-defective HCC1937 human breast cancer cells.

Germline mutations of the tumour suppressor gene BRCA1 are involved in the predisposition and development of breast cancer and account for 20-45% of all hereditary cases. There is an increasing evidence that these tumours are characterised by a specific phenotype and pattern of gene expression. We have hypothesised that differences in chemosensitivity might parallel molecular heterogeneity of hereditary and sporadic breast tumours. To this end, we have investigated the chemosensitivity of the BRCA1-defective HCC1937 breast cancer cell line, and the BRCA1-competent MCF-7 (hormone-sensitive) and MDA-MB231 (hormone-insensitive) breast cancer cell lines using the MTT assay. The 50% inhibitory concentration (IC(50)) for the individual compounds were derived by interpolate plot analysis of the logarithmic scalar concentration curve after a 48 h exposure. HCC1937 cells were significantly (P<0.005) more sensitive to cisplatin (CDDP) (IC(50) : 30-40 microM) compared with MCF-7 (IC(50) : 60-70 microM) and MDA-MB231 (IC(50) : 90-100 microM) cells. On the other hand, BRCA1-defective breast cancer cells were significantly less sensitive to doxorubicin (Dox) (IC(50) : 45-50 microM) compared with MCF-7 (IC(50) : 1-5 microM) and MDA-MB231 (IC(50) : 5-10 microM) (P<0.02), as well as to paclitaxel (Tax) (IC(50) : >2 microM for HCC1937, 0.1-0.2 microM for MCF-7 and 0.01-0.02 microM for MDA-MB231) (P<0.001). Full-length BRCA1 cDNA transfection of BRCA1-defective HCC1937 cells led to the reconstituted expression of BRCA1 protein in HCC1937/(WT)BRCA1-derived cell clone, but did not reduce tumour cell growth in soft agar. BRCA1 reconstitution reverted the hypersensitivity to CDDP (P<0.02), and restored the sensitivity to Dox (P<0.05) and Tax (P<0.001), compared with parental HCC1937 cells. Taken together, our findings suggest a specific chemosensitivity profile of BRCA1-defective cells in vitro, which is dependent on BRCA1 protein expression, and suggest prospective preclinical and clinical investigation for the development of tailored therapeutical approaches in this setting.

Low somatomedin activity in cord serum from infants with intrauterine growth retardation.

Somatomedin activity was determined by the simultaneous incorporation of 35S-sulfate and 3H-methyl thymidine into costal cartilage from hypophysectomized rats in cord sera from term and preterm infants and infants with intrauterine growth retardation. Mean Sm activity by sulfate incorporation was 0.49 +/- 0.04, 0.35 +/- 0.05, and 0.09 +/- 0.03 units/ml (+/- SE) in the term, preterm, and IGR cord sera, respectively. The levels for each group were significantly different from each of the other groups. There was no significant difference between the mean Sm activity by thymidine incorporation in cord sera from term (0.92 +/- 0.09 units/ml) and preterm (0.87 +/- 0.08 units/ml) infants. These levels were significantly higher, however, than the Sm activity by sulfate incorporation for the respective groups, P less than 0.001 for both groups. The mean Sm activity by thymidine incorporation in cord sera for IGR infants was 0.36 +/- 0.13 units/ml, and significantly lower than the levels in cord sera of term and preterm infants (P less than 0.01). Inhibition of Sm activity by mixing cord serum and pooled adult serum was found in one of the two cord specimens tested from IGR infants. The low levels of Sm activity in cord sera from IGR infants may reflect altered intrauterine nutrition. The discrepancy in the thymidine and sulfate incorporation by the costal cartilage bioassay for term and preterm cord sera might result from Sm-like factors in human fetal serum with greater mitogenic or thymidine transport activity compared to the activity for proteoglycan synthesis in cartilage.

Synthesis of -fetoprotein by liver, yolk sac, and gastrointestinal tract of the human conceptus.

PIP: Synthesis of serum alpha fetoprotein (AFP) was studied in 16 human embryos and fetuses from 4.2-18 weeks of gestation by incubation of selected tissues in radiolabeled amino acids followed by immunoelectrophoresis of the culture fluids and radioautography. Relatively large amounts of radioactive AFP, judged by relative intensity of AFP precipitation line on radioautography, were found in each of the liver cultures of the developing yolk sac. AFP was observed in smaller amounts in almost all gastrointestinal tract cultures studied. Labeled AFP formed in kidney cultures from 1 of 9 conceptuses and in only 1 of 14 placentas cultured. None of the cultures containing lung, thymus, pancreas, skeletal muscle, amnion, chorion, or blood produced detectable amounts of AFP.^ieng